Retinal degenerative diseases often lead to blindness due to lost neurons. A major goal of vision scientists is to restore these lost neurons. Due to their remarkable regenerative powers, zebrafish provide an ideal system for identifying strategies for restoring lost neurons in the retina. Although the zebrafish and mammalian retina are composed of similar cell types that are organized and function in a similar manner, they respond very differently to injury. Zebrafish respond to retinal damage by mounting a regenerative response that restores lost sight, while mammals do not. Key to the success of retina regeneration in zebrafish are Muller glia (MG) that respond to retinal damage by undergoing a reprogramming event that allows them to acquire properties of a stem cell. These reprogrammed MG are responsible for generating a multipotent proliferating population of retinal progenitors that regenerate all major retinal cell types. We propose that an understanding of the mechanisms by which MG reprogram to a retinal stem cell will help identify strategies for stimulating mammalian MG to undergo a similar transformation and repair a damaged retina. This proposal focuses on identifying these mechanisms with an emphasis on secreted factors regulating MG reprogramming and the gene expression programs that drive multipotency. It is anticipated that these studies will lead to novel strategies for inducing MG dedifferentiation and retina regeneration in mammals which may facilitate repairing a damaged or diseased human retina.